A wide variety of semi-synthetic aminoglycosidic antibiotics derived from kanamycin A, B or C has been known. Although these kanamycin derivatives known hithertobefore have useful antibacterial activities, their antibacterial spectra are of varying ranges, and the known kanamycin derivatives sometime may be ineffective against certain new resistant strains which may occur in future. It is hence always demaded to synthesize and provide new and still better antibacterial compounds.
We, the present inventors, succeeded in synthesizing a kanamycin A derivative having a fluorine atom substituted for the 3'-hydroxyl group, namely, 3'-deoxy-3'-fluorokanamycin A, and also we have observed that this compound is effective also against kanamycin-resistant bacteria (Japanese patent application No. 161615/84; Japanese patent application first publication "Kokai" No. 40297/86 and U.S. Pat. No. 4,634,688).
We also succeeded in synthesizing 3'-deoxy-3'-fluorokanamycin B and moreover, we confirmed that this novel compound has antibacterial activities against various gram-positive and gram-negative bacteria, including resistant strains (Japanese patent application No. 262700/84; Japanese patent application first publication "Kokai" No. 140597/86).
Also, we succeeded in making the synthesis of 3',4'-dideoxy-3'-fluorokanamycin B effective against such certain resistant strains of bacteria which produce enzymes capable of phosphorylating and/or capable of adenylating the 4'-hydroxyl group of 3'-deoxy-3'-fluorokanamycin B, for example, against Staphylococcus aureus Ap 01 and Staphylococcus epidermidis 109 (Japanese patent application No. 188525/85, Japanese patent application first publication "Kokai" No. 51694/87; U.S. patent application Ser. No. 899,100; and European patent application publication No. 0214904A2).
The present inventors also succeeded in producing 1-N-{(RS)- and (S)-3amino-2-hydroxypropionyl}- and 1-N-{(S)-4-amino-2-hydroxybutyry}-3'-deoxy-3'-fluorokanamycins A and B as novel compounds by acylating the 1-amino groups of these 3'-deoxy-3'-fluorokanamycins A and B with (RS)- or (S)-3-amino-2-hydroxypropionic acid or (S)-4-amino-2-hydroxybutyric acid, respectively. Moreover, it has been found that these novel compounds have antibacterial activities against gram-positive and gram-negative bacteria, including certain resistant strains of bacteria (see the specification of Japanese patent application No. 76706/85 and Japanese patent application first publication "Kokai" No. 236791/86).
As a result of a further investigation, the present inventors also succeeded firstly in synthesizing 2',3'-dideoxy-2'-fluorokanamycin A, and moreover we confirmed that this novel compound has antibacterial activities against gram-positive and gram-negative bacteria, including certain resistant strains of bacteria (see the specification of Japanese patent application No. 263759/84; Japanese patent application first publication "Kokai" No. 143393/86; U.S. Pat. No. 4,661,474; and European patent application publication No. 0185323A2). Also the present inventors succeeded in producing 1-N-{(RS)- and (S)-3-amino-2-hydroxypropionyl}-and 1-N-{(S)-4-amino-2-hydroxybutyl}-2', 3'-dideoxy-2'-fluorokanamycins A as novel compounds by acylating the 1-amino group of the 2',3'-dideoxy-2'-fluorokanamycin A, with (RS)- or (S)-3-amino-2-hydroxypropionic acid or (S)-4-amino-2-hydroxybutyric acid, respectively. Moreover, we have observed that these novel compounds have excellent antibacterial activities against gram-positive and gram-negative bacteria, including certain resistant strains of bacteria (European patent application Publication No. 0185323A2 and U.S. Pat. No. 4,661,474).
Further, we also succeeded in synthesizing 5-deoxy-5-fluorokanamycin B as a novel compound from kanamycin B and found that 5-deoxy-5-fluorokanamycin B has antibacterial activities as enhanced or improved advantageously over kanamycin B (Japanese patent application No. 181850/86, U.S. patent application Ser. No. 078,996; European patent application No. 87306904.1). We have also succeeded in synthesizing 5,3'-dideoxy-5-fluorokanamycin B from 3'-deoxykanamycin B (i.e., tobramycin), 5,4'-dideoxy-5-fluorokanamycin B from 4'-deoxykanamycin B, and 5,3',4'-trideoxy-5-fluorokanamycin B from 3',4'-dideoxykanamycin B (i.e., dibekacin). The present inventors also have made the acylation of the 1-amino group of 5-deoxy-5-fluorokanamycin B, 5,3'-dideoxy-5-fluorokanamycin B, 5,4'-dideoxy-5-fluorokanamycin B and 5,3',4'-trideoxy-5-fluorokanamycin B with (RS)-or (S)-3-amino-2-hydroxypropionyl or (S)-4-amino-2-hydroxybutyryl groups, respectively, so that their corresponding 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl) derivatives are produced as novel compounds. We have also found that the latter new 1-N-acylated derivatives have further improved antibacterial activities (Japanese patent application No. 181850/86 and U.S. patent application Ser. No. 078,996 referred to above).
On the other hand, it is known that when an aminoglycosidic antibiotic acts on bacteria under acidic conditions, the antibacterial activity of this antibiotic can be decreased or become substantially null against the bacteria, even though said antibiotic can show a high and effective antibacterial activity against the bacteria when it acts on the bacteria under neutral or weakly alkaline conditions. The bacterially infected local parts (the bacterial lesions) of the living human body are not always to exist under neutral condition (pH 7.0) but may sometime exist under acidic conditions of pH 6 or more acidic conditions.
There is hence an outstanding demand for the development of such an antibacterial aminoglycosidic antibiotic or a semisynthetic derivative thereof, which can exhibit high and reliable antibacterial activities sufficient to kill bacteria effectively even when the antibacterial compound acts on the bacteria under acidic conditions of pH 6-7.